What alternative anticoagulant should be used for a 68-year-old woman with an estimated glomerular filtration rate of 22 mL/min and a history of prior deep‑vein thrombosis who is having problems with apixaban (Eliquis)?

Alternative Anticoagulation for Severe Renal Impairment with Prior DVT

Switch to warfarin with a target time-in-therapeutic-range (TTR) >65–70%, as this remains the guideline-recommended first-line anticoagulant for patients with creatinine clearance <30 mL/min who cannot tolerate apixaban. 1

Immediate Assessment

• Calculate creatinine clearance using the Cockcroft-Gault equation (not eGFR), as this is the validated method for anticoagulant dosing decisions and was used in all pivotal trials. 1

• With a GFR of 22 mL/min, this patient has CKD Stage 4 (CrCl 15–29 mL/min), which mandates specific dosing considerations for all anticoagulants. 1

• Determine the nature of the "caused issues" with Eliquis: bleeding complications, gastrointestinal intolerance, cost barriers, or other adverse effects will guide the choice of alternative therapy.

Primary Recommendation: Warfarin

Warfarin is the preferred alternative anticoagulant for patients with CrCl 15–30 mL/min who cannot continue apixaban, as it does not rely on renal clearance and has the most extensive safety data in advanced CKD. 1

• Target an INR of 2.0–3.0 for VTE treatment, with meticulous monitoring to maintain TTR >65–70%, as lower TTR is associated with increased thrombotic and bleeding complications in CKD patients. 1

• Warfarin carries a significantly increased bleeding risk in ESKD (approximately twice the rate of anticoagulant-related nephropathy compared to patients without renal disease) and promotes vascular calcification by inhibiting Matrix Gla Protein. 1

• Despite these risks, warfarin remains guideline-recommended because it is the only oral anticoagulant with decades of outcome data in severe CKD, unlike DOACs which were excluded from pivotal trials at this level of renal function. 1

Alternative Option: Continue Apixaban at Reduced Dose

If the "issues" with Eliquis were related to standard dosing rather than intolerance, consider apixaban 2.5 mg twice daily, as this is the FDA-approved dose for CrCl 15–29 mL/min. 1

• For CKD Stage 4 (CrCl 15–29 mL/min), apixaban 2.5 mg twice daily is recommended for all patients, regardless of age, weight, or serum creatinine, because severe renal impairment alone mandates dose reduction. 1

• Apixaban has only 27% renal clearance, making it the DOAC with the lowest renal dependence compared to dabigatran (≈80%) or rivaroxaban (≈66%), which provides a wider safety margin as kidney function declines. 1

• A 2023 meta-analysis of patients with severe renal failure showed apixaban reduced VTE recurrence by 35% (RR 0.65,95% CI 0.43–0.98) and major bleeding by 28% (RR 0.72,95% CI 0.62–0.84) compared to warfarin. 2

• A 2022 national cohort study of ESKD patients with acute VTE found apixaban was associated with lower major bleeding (HR 0.81,95% CI 0.70–0.94), intracranial hemorrhage (HR 0.69,95% CI 0.48–0.98), and gastrointestinal bleeding (HR 0.82,95% CI 0.69–0.96) compared to warfarin, with no difference in recurrent VTE or mortality. 3

Agents to Avoid

• Do not use dabigatran, as it is contraindicated in Europe for CrCl <30 mL/min and has 80% renal clearance, leading to excessive drug accumulation and bleeding risk. 1

• Do not use rivaroxaban at this level of renal function, as it has 66% renal clearance and is approved only down to CrCl 30 mL/min for VTE treatment. 1

• Do not use edoxaban, as it is absolutely contraindicated in ESRD or dialysis due to 50% renal excretion and excessive drug accumulation. 4

• Do not use low-molecular-weight heparin (LMWH) for long-term therapy, as it accumulates unpredictably in severe renal impairment and requires anti-Xa monitoring, which is cumbersome and not well-validated in this setting. 5

Monitoring and Follow-Up

• Reassess renal function every 3–6 months (or more frequently if clinical deterioration occurs), as 29% of patients with CKD require anticoagulant dose adjustments during follow-up due to changing renal parameters. 1

• If using warfarin, check INR weekly until stable, then at least monthly, with more frequent monitoring during intercurrent illness or medication changes. 1

• If continuing apixaban 2.5 mg twice daily, monitor for bleeding symptoms (particularly gastrointestinal and intracranial), as routine laboratory monitoring is not required but clinical vigilance is essential. 1

• Screen for drug interactions: avoid combined P-glycoprotein and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) with apixaban, and avoid strong CYP3A4 inducers (e.g., rifampin) entirely. 1

Common Pitfalls

• Do not reduce apixaban below 2.5 mg twice daily based on perceived bleeding risk or frailty, as this is already the evidence-based reduced dose for severe renal impairment and further reduction lacks safety data. 1

• Do not rely on eGFR for dosing decisions, as it is not interchangeable with creatinine clearance and can lead to significant dosing errors; always use Cockcroft-Gault. 1

• Do not assume the "2-of-3" dose-reduction criteria apply at this level of renal function, as those criteria (age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL) are only relevant when CrCl >30 mL/min; severe renal impairment alone mandates the 2.5 mg dose. 1

• If the patient progresses to dialysis (CrCl <15 mL/min), warfarin becomes the preferred first-line agent, though apixaban 5 mg twice daily (reduced to 2.5 mg if age ≥80 years OR weight ≤60 kg) is FDA-approved in the United States for stable hemodialysis patients. 1, 6